This application is submitted on behalf of the Lymphoma and Leukemia Molecular Profiling Project (LLMPP), a long-standing, tightly integrated, international research consortium based in the United States with a highly successful track-record of discovery and clinical translation profoundly impacting the known biology, classification, and treatment of lymphoma. In the current application, we propose 4 complimentary projects to extend our understanding of difficult to treat lymphomas including (1) Aggressive B cell lymphomas (Dr. Scott), (2) Mantle cell lymphoma (Dr. Campo), (3) Peripheral T cell lymphoma (Dr. Iqbal), and (4) Anaplastic large cell lymphoma (Dr. Feldman). The overall research strategy will extend our gene expression characterization and initial sequencing studies into larger more comprehensive analyses of genomics (including sequence, rearrangements, copy number variations, and epigenetics) in order to identify new diagnostic categories with unique biological features, prognoses, and therapeutic targets. In Aggressive B cell lymphomas there is a pressing need to understand the appropriate diagnostic categorization as related to treatment failure. Mantle cell lymphoma has an extremely variable range of outcomes from slow growing tumors requiring minimal therapy to those requiring transplant and thus likely represents more than one disease. Peripheral T cell lymphoma-Not otherwise specified is a nearly orphan disease with few patients surviving despite intense therapy. Anaplastic large cell lymphoma is a rare disease with variable outcome and different genetics in adults versus children. The Projects' details are described in additional abstracts. We overall hypothesize that aggressive B and T cell lymphomas can be further subdivided by genomic alterations including translocation partners, breakpoints, mutations, copy number alterations, epigenetics, and phenotype and that these features can be functionally characterized and used to improve patient care. As in our prior work, the bedrock of these translational projects will be sophisticated analyses of primary tissue biopsies from patients that are communally reviewed by a panel of pathologists for accurate diagnosis, quality, and tumor content. The individual scientific projects of this grant will synergize by sharing tissues, scientific strategies, data, analysis techniques, and assay development expertise. This teamwork will be complimented by functional genomics and patient derived tumor xenograft systems for pre- clinical modeling. The Projects will work closely with biostatistics for study design and analysis and use bioinformatics to analyze high throughput data. Thus, the proposed cores include Administrative (Dr. Rimsza), Pathology (Dr. Cook), Functional Genomics (Dr. Staudt), Preclinical Models and Therapeutics (Dr. Inghirami) and Biostatistics & Bioinformatics (Dr. Wright). The overall intention is to use genomic studies as a platform to better understand disease biology, develop more correct classification and prognosis, and identify and characterize therapeutic targets; with a long-term goal of enhancing patient survival.